anandamide and Morphine-Dependence

Nicotine in tobacco, tetrahydrocannabinol (delta 9-THC) in marijuana and morphine in opium are well known as drugs associated with dependence or addiction. Endogenous active substances that mimic the effects of the natural drugs and their respective receptors have been found in the mammalian central nervous system (CNS). Such active substances and receptors include acetylcholine (ACh) and the nicotinic ACh receptor (nAChR) for nicotine, anandamide and CB1 for delta 9-THC, and endomorphins (1 and 2) and the mu (OP3) opioid receptor for morphine, respectively. Considerable progress has been made in studies on neurotoxicity, in terms of the habituation, dependence and withdrawal phenomena associated with these drugs and with respect to correlations with endogenous active substances and their receptors. In this article we shall review recent findings related to the neurotoxicity of tobacco, marijuana and opium, and their toxic ingredients, nicotine, delta 9-THC and morphine in relation to their respective endogenous agents and receptors in the CNS.

Topics: Acetylcholine; Arachidonic Acids; Brain Chemistry; Cannabis; Dronabinol; Endocannabinoids; Endorphins; Humans; Marijuana Abuse; Morphine; Morphine Dependence; Nicotine; Opium; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug; Receptors, Nicotinic; Receptors, Opioid; Tobacco Use Disorder

It has been suggested recently that the endocannabinoid system might be a component of the brain reward circuitry and thus play a role not only in cannabinoid tolerance/dependence, but also in dependence/withdrawal to other drugs of abuse. Here we have examined the changes in endocannabinoid ligands and their receptors in different brain regions, with particular attention to those areas related to reinforcement processes, during dependence on the powerful addictive drug, morphine. Thus, we analysed the brain contents of N-arachidonoylethanolamine (anandamide, AEA), the first discovered endocannabinoid, in rats subjected to daily injections of increasing doses of morphine, according to a schedule designed to render the animals opiate-dependent. Although evidence of physical dependence was assured by the appearance of somatic and neurovegetative responses in these animals after an acute challenge with naloxone, there were no changes in the contents of this endocannabinoid in any of the brain regions analysed. By contrast, we observed a significant decrease in the specific binding for CB(1) receptors in the midbrain and the cerebral cortex of morphine-dependent rats, with no changes in the other regions. The decrease in the cerebral cortex was, however, accompanied by a rise in the activation of signalling mechanisms by CB(1) receptor agonists, as revealed by WIN-55,212-2-stimulated [(35)S]GTPgammaS binding, whereas a reduction in this parameter was measured in the brainstem of morphine-dependent rats. In summary, the present data are indicative of the existence of an alteration of the endocannabinoid transmission during morphine dependence in rats, although the changes observed were region-dependent and affected exclusively CB(1) receptors with no changes in endocannabinoid levels. Because the changes occurred in regions of the midbrain, the cerebral cortex and the brainstem, which have been implicated in drug dependence, our data suggest that pharmacological manipulation of the endocannabinoid system might be a novel tool to reduce morphine addiction.

Topics: Analgesics; Animals; Arachidonic Acids; Benzoxazines; Binding Sites; Cannabinoid Receptor Modulators; Cerebral Cortex; Corpus Striatum; Drug Administration Schedule; Endocannabinoids; Injections, Intravenous; Male; Mesencephalon; Morphine; Morphine Dependence; Morpholines; Naphthalenes; Narcotics; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Reinforcement, Psychology; Signal Transduction; Synaptic Transmission

The endogenous cannabinoid, anandamide, has been shown to attenuate naloxone-precipitated opiate withdrawal in rodents. Here we show that the spontaneous, but not the naloxone-precipitated withdrawal syndrome in morphine-dependent mice is attenuated by the inhibitor of carrier-mediated anandamide transport N-(4-hydroxyphenyl) arachidonylethanolamide (AM404) (2 and 10 mg/kg, i.p.). These results suggest that spontaneous but not opioid antagonist-precipitated withdrawal is associated with dynamic changes in endogenous cannabinoid signaling.

Topics: Animals; Arachidonic Acids; Biological Transport; Depression, Chemical; Dose-Response Relationship, Drug; Endocannabinoids; Mice; Morphine Dependence; Naloxone; Narcotic Antagonists; Polyunsaturated Alkamides; Substance Withdrawal Syndrome